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Etudes relatives aux modèles cellulaires et animaux :
Les investigations envisagées sur les lignées cellulaires SQ20B et SCC90 sont la UpDOLVDWLRQ G¶H[SpULHQFHV G¶LQKLELWLRQ GH O¶H[SUHVVLRQ GH +,)Į par ARN interférent, afin de GpWHUPLQHUODSDUWGHUpJXODWLRQGHFHIDFWHXUGDQVO¶LQGXFWLRQGHVJqQHVHQK\SR[LHWDUGLYH
IOVHUDLWpJDOHPHQWLQWpUHVVDQWG¶pYDOXHUODQDWXUHGHODPRUWFHOOXODLUHTXHQRXVREVHUYRQV dans la lignée HPV positive SCC90/¶DQDO\VHGHO¶DSRSWRVHDXFRXUVGHO¶K\SR[LHSRXUUDLWrWUH UpDOLVpHHQPHVXUDQWO¶DFWLYLWpGHVFDVSDVHVHW/¶DXWRSKDJLHSRXUUDLWrWUHDQDO\VpHSDUO¶pWXGH GH O¶H[SUHVVLRQ G¶XQH SURWpLQH GH IXVLRQ /&-GFP (Microtubule-associated protein 1A/1B-light chain 3 Green Fluorescent Protein GDQV GHV FHOOXOHV WUDQVIHFWpHV /¶H[SUHVVLRQ GH OD SURWpLQH /&HVWLQGXLWHDXFRXUVGHO¶DXWRSKDJLH&HWWHSURWpLQHHVWUHFUXWpHDXQLYHDXGHODPHPEUDQH des autophagosomes.
De plus, il pourrait être intéressant de réaliser les transfections pour le test luciférase et de mesurer par qRT-3&5OHVQLYHDX[G¶H[SUHVVLRQGHVJqQHVGHO¶DSRSWRVHGHO¶DXWRSKDJLHGHp21 et de Mdm2 DXFRXUVGHODFLQpWLTXHG¶K\SR[LHDILQGHGpWHUPLQHUV¶LOH[LVWHXQHGLIIpUHQFHGDQVOH QLYHDXG¶H[SUHVVLRQSDUUDSSRUWDX[H[SpULHQFHVVDQVWUDQVIHFWLRQG¶DQDO\VHGHODPRUWFHOOXODLUH
Il serait pertinent dans les cellules SCC90 (lignée exprimant une version sauvage du gène TP53 G¶LQKLEHUO¶DFWLYLWpGHSSDU$51LQWHUIpUHQWHWGHPHVXUHUOHVQLYHDX[G¶H[SUHVVLRQGHV JqQHV GH OD JO\FRO\VH HQ K\SR[LH DILQ GH FRPSDUHU FHV QLYHDX[ G¶H[SUHVVLRQ DYHF OD OLJQpH SQ20B exprimant une version non fonctionnelle de la protéine p53 et de déterminer la part de régulation de p53 dans le métabolisme du glucose.
3OXVLHXUV SUREOqPHV G¶RUGUH WHFKQLTXH UHQFRQWUpV DX FRXUV G¶DQDO\VHV SDU ZHVWHUQ EORW (dégradations protéiques, bruit de fond important, signaux aspécifiques) nous ont empêchés de PHQHU j ELHQ QRV WHQWDWLYHV GH TXDQWLILFDWLRQV GH O¶H[SUHVVLRQ GHV SURWpLQHs Net, Elk1 et Sap1 dans les deux lignéeV FHOOXODLUHV ,O V¶DYqUH GRQF QpFHVVDLUH de réaliser des expériences de VXUH[SUHVVLRQHWG¶LQYDOLGDWLRQGHO¶H[SUHVVLRQGHFHVWURLVIDFWHXUVGHWUDQVFULSWLRQSRXULGHQWLILHU avec certitude, par western blot, le sigQDOFRUUHVSRQGDQWVSpFLILTXHPHQWDX[SURWpLQHVG¶LQWpUrW
En perspective, il serait intéressant de réaliser des expériences de surexpression et G¶LQYDOLGDWLRQGHO¶H[SUHVVLRQGHFHVWURLVIDFWHXUVGHWUDQVFULSWLRQ :
- DILQG¶pYDOXHUOHVQLYHDX[G¶H[SUHVVLRQ des gènes et des protéines de c-Fos et Fra-2 en normoxie et en hypoxie. Ces expériences permettraient de déterminer si la diminution GHO¶H[SUHVVLRQGHVIDFWHXUV7&)OqYHO¶LQKLELWLRQVXUF-Fos ou Fra-2.
- afin de caractériser une potentielle relation inverse entre un des facteurs TCF (Net, Elk1 RX6DS G¶XQHSDUWF-Fos ou Fra-G¶DXWUHSDUWGDQVODOLJQpH64%
Le développement de modèles animaux au moyen de nouvelles xénogreffes en injectant les lignées cellulaires SQ20B et SCC90 sur des rats Nude permettra de mesurer et de visualiser,
163
par imagerie en temps réel, O¶K\SR[LH LQWUDWXPRUDOH SDU PDUTXDJH DX )0,62 [18 F]-Fluoromisonidazole) grâce à un PET-SCAN du petit animal situé sur la plateforme du Nancyclotep à Nancy.
Etudes relatives aux tumeurs humaines oropharyngées :
Une des perspectives de notre étude sur les tumeurs VHUD G¶pWXGLHU OD VWUXFWXUH GH FHV vaisseaux sanguins dans les deux groupes de tumeurs oropharyngées, afin de déterminer si ces vaisseaux tumoraux sont fonctionnels, en marquant les péricytes, localisés au niveau de la lame EDVDOH GH O¶HQGRWKpOLXP YDVFXODLUH HW TXL FRQWULEXHQW j OD VWDELOLWp GH OD VWUXFWXUH YDVFXODLUH /¶DUFKLWHFWXUHYDVFXODLUHSHXWrWUHYLVXDOLVpHSDUPDUTXDJHLPPXQRKLVWRFKLPLTXHjO¶DLGH
- d¶XQDQWLFRUSVDQWL-Tie2, un récepteur transmembranaire des cellules endothéliales. - d¶XQDQWLFRUSVDQWL-$QJ DQJLRSRLpWLQH TXLHVWXQGHVOLJDQGVGH7LH/¶$QJSHUPHW
le recrutement et la maturation des péricytes.
Dans les tumeurs oropharyngées HPV positives, il reste également à déterminer :
- OHU{OHGHVRQFRSURWpLQHVYLUDOHVG¶+39GDQVODVWDELOLVDWLRQGHOD SURWpLQH+,)Į - OH U{OH G¶+39 GDQV O¶DQJLRJHQqVH DFFUXH GDQV OHV WXPHXUV RURSKDU\QJpHV :
O¶DQJLRJHQqVH DFFUXH HVW-elle un processus spécifique caractéristique de la formation des tumeurs oropharyngées induite par HPV ?
CONCLUSION GENERALE.
$X YX GH O¶HQVHPEOH GHV UpVXOWDWV obtenus au cours de ma thèse, il apparaît que les tumeurs oropharyngées HPV positives présentent un statut hypoxique moindre et une vascularisation tumorale plus abondante comparées aux tumeurs oropharyngées HPV négatives. /HV PDUTXHXUV OHV SOXV SHUWLQHQWV SRXU pYDOXHU O¶K\SR[LH LQWUDWXPRUDOH GDQV OHV WXPHXUV oropharyngées semblent être :
- O¶DQDO\VHGHO¶H[SUHVVLRQGHVJqQHV+,)Į3+', GLUT1, PAI-1 et NDRG1 par qRT-PCR.
- O¶DQDO\VH GH O¶H[SUHVVLRQ SURWpLTXH GH CA-IX (hypoxie) et de CD105 (angiogenèse tumorale) par immunohistochimie.
Parallèlement à cette signature moléculaire du statut hypoxique, les tumeurs oropharyngées HPV positives présentent également une importante infiltration lymphocytaire T CD8+ et Trég CD4+, corrélée à une survie améliorée. Il conviendra donc G¶évaluer j O¶DYHQLU O¶LQWHUDFWLRQHQWUHcette réponse immunitaire par infiltration de lymphocytes T CD8+ et CD4+ et la présence de régions tumorales hypoxiques des tumeurs des VADS.
Le statut de moindre hypoxie associé à un meilleur pronostic implique d¶en les caractéristiques moléculaires pour distinguer les catégories de tumeurs des VADS. Par ailleurs, les tumeurs des VADS ont des pronostics différents selon leur statut HPV. La détermination du statut HPV dans les échantillons tumoraux devrait UHSRVHU VXU OD GpWHFWLRQ GH O¶$'1 G¶+39 HW GH O¶H[SUHVVLRQGHVWUDQVFULWV(HW(G¶+PVWpPRLQG¶XQYLUXVWUDQVFULSWLRQQHOOHPHQWDFWLI.
La distinction des différents groupes de tumeurs des VADS en fonction de leur statut HPV et de leur caractéristiques hypoxiques devrait permettre de :
- de mieux évaluer l¶impact des différents protocoles d¶essais thérapeutiques
- de proposer des désescalades de doses en radiothérapie et en chimiothérapie, pour en atténuer les effets secondaires, aux patients ayant une tumeur HPV positive non hypoxique ou faiblement hypoxique.
- d¶DPpOLRUHU la réponse des tumeurs HPV négatives et HPV positives fortement hypoxiques aux traitements de radiothérapie en utilisant des molécules radiosensibilisatrices spécifiques des régions hypoxiques, telles que le nimorazole ou le FAZA.
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1. Cancer, I.N.d., Les cancers en France. Edition 2013.
2. Chaturvedi, A.K., et al., Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol, 2011. 29(32): p. 4294-4301.
3. Ramqvist, T. and T. Dalianis, Oropharyngeal cancer epidemic and human papillomavirus. Emerg Infect Dis, 2010. 16(11): p. 1671-7.
4. Hammarstedt, L., et al., Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer, 2006. 119(11): p. 2620-3.
5. Lindel K, et al., Human Papillomavirus Positive Squamous Cell Carcinoma of the Oropharynx. Cancer 2001. 92(4): p. 805-813.
6. Jung, A.C., et al., CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis. Int J Cancer, 2013.
132(2): p. E26-36.
7. Lassen, P., et al., HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer. Radiother Oncol, 2010. 94(1): p. 30-5.
8. Chen, L., A. Endler, and F. Shibasaki, Hypoxia and angiogenesis: regulation of hypoxia-inducible factors via novel binding factors. Exp Mol Med, 2009. 41(12): p. 849-857.
9. Harris, A.L., Hypoxia : a key regulatory factor in tumour growth. Nat Rev Cancer, 2002.
2(1): p. 38-47.
10. Semenza, G.L., Targeting HIF-1 for cancer therapy. Nat Rev Cancer, 2003. 3(10): p. 721-32.
11. Bose, P., N.T. Brockton, and J.C. Dort, Head and neck cancer: from anatomy to biology. Int J Cancer, 2013. 133(9): p. 2013-2023.
12. Argiris A., et al., Head and neck cancer. The Lancet, 2008. 371(9625): p. 1695-1709. 13. Pai, S.I. and W.H. Westra, Molecular pathology of head and neck cancer: implications for
diagnosis, prognosis, and treatment. Annu Rev Pathol, 2009. 4: p. 49-70.
14. Neufcoeur, P.E., et al., Involvement of human papillomavirus in upper aero-digestive tracts cancers. Bull Cancer, 2009. 96(10): p. 941-50.
15. Gandini, S., et al., Tobacco smoking and cancer: a meta-analysis. Int J Cancer, 2008.
122(1): p. 155-164.
16. Vineis, P., et al., Tobacco and Cancer: Recent Epidemiological Evidence. JNCI Journal of the National Cancer Institute, 2004. 96(2): p. 99-106.
17. Hashibe, M., et al., Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst, 2007. 99(10): p. 777-89. 18. Macfarlane G.J. , et al., Alcohol, Tobacco, Diet and the Risk of Oral Cancer: a Pooled
Analysis of Three Case-Control Studies. Oral Oncol, Euro J Cancer, 1995. 31B(3): p. 181-187.
19. Hashibe, M., et al., Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev, 2009. 18(2): p. 541-50.
20. Hill, C., Epidémiologie des cancers des voies aérodigestives supérieures. Bulletin du Cancer, 2000. 87.
21. Franceschi S, et al., Smoking and Drinking in Relation to Cancers of the Oral Cavity, Pharynx, Larynx, and Esophagus in Northern Italy. Cancer Research, 1990. 50: p. 6502-6507.
22. Leemans, C.R., B.J. Braakhuis, and R.H. Brakenhoff, The molecular biology of head and neck cancer. Nat Rev Cancer, 2011. 11(1): p. 9-22.
23. '¶6RX]D * HW DO Case±Control Study of Human Papillomavirus and Oropharyngeal Cancer. The new england journal of medicine, 2007. 356(19): p. 1944-1956.
24. Gillison M.L., et al., Evidence for a Causal Association Between Human Papillomavirus and a Subset of Head and Neck Cancers. Journal of the National Cancer Institute, 2000. 92(9): p. 709-720.
25. Gillison, M.L., et al., Human papillomavirus and diseases of the upper airway: head and neck cancer and respiratory papillomatosis. Vaccine, 2012. 30 Suppl 5: p. 34-54.
26. Maalouf, M., et al., Different mechanisms of cell death in radiosensitive and radioresistant p53 mutated head and neck squamous cell carcinoma cell lines exposed to carbon ions and x-rays. Int J Radiat Oncol Biol Phys, 2009. 74(1): p. 200-209.
167
27. Bjorge T., et al., Second primary cancers in patients with carcinoma in situ of the uterine cervix. The Norwegian experience 1970-1992. Int. J. Cancer, 1996. 62: p. 29-33.
28. Franceschi S, et al., Human papillomavirus and cancers of the upper aerodigestive tract: a review of epidemiological and experimental evidence. Cancer Epidemiol Biomarkers Prev, 1996. 5: p. 567-575.
29. Warnakulasuriya, S., Is human papillomavirus a risk factor for oral squamous cell carcinoma ? Evidence-Based Dentistry, 2003. 4(2): p. 29-29.
30. L., G.M., et al., Human papillomavirus in head and neck squamous cell carcinoma: are some head and neck cancers a sexually transmitted disease? Curr Opin Oncology, 1999. 31. Smeets, S.J., et al., Immortalization of oral keratinocytes by functional inactivation of the
p53 and pRb pathways. Int J Cancer, 2011. 128(7): p. 1596-605.
32. Gillison, M.L., et al., Prevalence of oral HPV infection in the United States, 2009-2010. JAMA, 2012. 307(7): p. 693-703.
33. Worden, F.P., et al., Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol, 2008. 26(19): p. 3138-46.
34. Gillison, M.L., et al., Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst, 2008. 100(6): p. 407-420.
35. Heck, J.E., et al., Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol, 2010. 39(1): p. 166-81.
36. de Villiers, E.M., et al., Classification of papillomaviruses. Virology, 2004. 324(1): p. 17-27. 37. Bonner J. A., et al., Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the
Head and Neck. The new england journal of medicine, 2008. 354(6): p. 567-578.
38. De Villiers, E.M., Cross-roadsintheclassification ofpapillomaviruses. Virology, 2013. 445. 39. Mougin C., Nicoliera M, and D.-B. AZ., +39 HW FDQFHUV PpFDQLVPHV GH O¶RQFRJHQqVH
Revue Francophone des Laboratoires, 2008. 405: p. 35-42.
40. Sapp, M. and M. Bienkowska-Haba, Viral entry mechanisms: human papillomavirus and a long journey from extracellular matrix to the nucleus. FEBS J, 2009. 276(24): p. 7206-16. 41. Rautava, J. and S. Syrjanen, Biology of human papillomavirus infections in head and neck
carcinogenesis. Head Neck Pathol, 2012. 6 Suppl 1: p. S3-15.
42. Prétet, J.-L., et al., Human papillomavirus (HPV) genotype distribution in invasive cervical cancers in France : EDITH study. Int J Cancer, 2008. 122: p. 428-432.
43. Doorbar, J., The papillomavirus life cycle. J Clin Virol, 2005. 32 Suppl 1: p. S7-15.
44. Letian, T. and Z. Tianyu, Cellular receptor binding and entry of human papillomavirus. Virol J, 2010. 7: p. 2.
45. Bousarghin L, et al., Human Papillomavirus Types 16, 31, and 58 Enter Cells Use Different Endocytosis Pathways To. Journal of virology, 2003. 77(6): p. 3846-3850.
46. Raybould R, Fiander A, and H. S, Human Papillomavirus Integration and its Role in Cervical Malignant Progression. The Open Clinical Cancer Journal, 2011. 5: p. 1-7.
47. Prétet J-L, Charlot J-F, and M. C, Aspects virologiques et carcinologiques des papillomavirus humains HPV. Bull. Acad. Natle Méd, 2007. 191: p. 611-623.
48. Kreimer, A.R., et al., Oral human papillomavirus in healthy individuals: a systematic review of the literature. Sex Transm Dis, 2010. 37(6): p. 386-91.
49. Kreimer, A.R., et al., The epidemiology of oral HPV infection among a multinational sample of healthy men. Cancer Epidemiol Biomarkers Prev, 2011. 20(1): p. 172-82.
50. Duray A, et al., High prevalence of high-risk human papillomavirus in palatine tonsils from healthy children and adults. Otolaryngol Head Neck Surg, 2011. 145(2).
51. Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. Cell, 2011.
144(5): p. 646-74.
52. Califano J, et al., Genetic Progression Model for Head and Neck Cancer: Implications for Field Cancerization. Cancer research, 1996. 56: p. 2488-2492.
53. Argiris, A., et al., Head and neck cancer. The Lancet, 2008. 371(9625): p. 1695-1709. 54. Majchrzak, E., et al., Oral cavity and oropharyngeal squamous cell carcinoma in young
55. Braakhuis, B.J.M., et al., Genetic Patterns in Head and Neck Cancers That Contain or Lack Transcriptionally Active Human Papillomavirus. Journal of the National Cancer Institute, 2004. 96(13): p. 998-1006.
56. Smeets, S.J., et al., Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus. Oncogene, 2006. 25(17): p. 2558-64.
57. Licitra, L., et al., High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol, 2006. 24(36): p. 5630-6. 58. Agrawal, N., et al., Exome sequencing of head and neck squamous cell carcinoma reveals
inactivating mutations in NOTCH1. Science, 2011. 333(6046): p. 1154-1157.
59. Stransky, N., et al., The mutational landscape of head and neck squamous cell carcinoma. Science, 2011. 333(6046): p. 1157-60.
60. Ragin, C.C., et al., 11q13 amplification status and human papillomavirus in relation to p16 expression defines two distinct etiologies of head and neck tumours. Br J Cancer, 2006.
95(10): p. 1432-8.
61. Sisk EA, et al., Human papillomavirus and p53 mutational status as prognostic factors in head and neck carcinoma. Head and Neck, 2002. 24(9): p. 841-849.
62. Smith, E.M., et al., Association between p53 and human papillomavirus in head and neck cancer survival. Cancer Epidemiol Biomarkers Prev, 2008. 17(2): p. 421-7.
63. Westra, W.H., et al., Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck. Clin Cancer Res, 2008. 14(2): p. 366-9.
64. Deshpande, A.M. and D.T. Wong, Molecular mechanisms of head and neck cancer. Expert Rev Anticancer Ther, 2008. 8(5): p. 799-809.
65. Partridge, M., D.E. Costea, and X. Huang, The changing face of p53 in head and neck cancer. Int J Oral Maxillofac Surg, 2007. 36(12): p. 1123-38.
66. Charfi, L., et al., Two types of squamous cell carcinoma of the palatine tonsil characterized by distinct etiology, molecular features and outcome. Cancer Lett, 2008. 260(1-2): p. 72-78. 67. Ritchie, J.M., et al., Human papillomavirus infection as a prognostic factor in carcinomas of
the oral cavity and oropharynx. Int J Cancer, 2003. 104(3): p. 336-44.
68. Hong, A., et al., Relationships between epidermal growth factor receptor expression and human papillomavirus status as markers of prognosis in oropharyngeal cancer. Eur J Cancer, 2010. 46(11): p. 2088-96.
69. Shi, W., et al., Comparative prognostic value of HPV16 E6 mRNA compared with in situ hybridization for human oropharyngeal squamous carcinoma. J Clin Oncol, 2009. 27(36): p. 6213-21.
70. Lau, H.Y., et al., Prognostic significance of p16 in locally advanced squamous cell carcinoma of the head and neck treated with concurrent cisplatin and radiotherapy. Head Neck, 2011. 33(2): p. 251-6.
71. Mellin H, et al., Human papillomavirus (HPV) DNA in tonsillar cancer : clinical correlates, risk of relapse and survival. Int J Cancer, 2000. 89: p. 300±304.
72. Ernster J.A., et al., Rising Incidence of Oropharyngeal Cancer and the Role of Oncogenic Human Papilloma Virus. The Laryngoscope, 2007. 117: p. 2115-2128.
73. Maxwell, J.H., et al., Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res, 2010. 16(4): p. 1226-35.
74. Schwartz, S.R., et al., Human papillomavirus infection and survival in oral squamous cell cancer: a population-based study. Otolaryngol Head Neck Surg, 2001. 125(1): p. 1-9. 75. Ang, et al., Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer.
The New england journal of medicine, 2010. 361(1): p. 24-36.
76. Hafkamp, H.C., et al., Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas. Int J Cancer, 2008. 122(12): p. 2656-64.
77. Furniss, C.S., et al., Human papillomavirus 16 and head and neck squamous cell carcinoma. Int J Cancer, 2007. 120(11): p. 2386-2392.
78. Chien, C.Y., et al., Lower prevalence but favorable survival for human papillomavirus-related squamous cell carcinoma of tonsil in Taiwan. Oral Oncol, 2008. 44(2): p. 174-179.
169
79. Straetmans, J.M., et al., Human papillomavirus reduces the prognostic value of nodal involvement in tonsillar squamous cell carcinomas. Laryngoscope, 2009. 119(10): p. 1951-7.
80. Zhao, D., et al., Human papillomavirus as an independent predictor in oral squamous cell cancer. Int J Oral Sci, 2009. 1(3): p. 119-25.
81. Nichols, A.C., et al., Bcl2 and human papilloma virus 16 as predictors of outcome following concurrent chemoradiation for advanced oropharyngeal cancer. Clin Cancer Res, 2010.
16(7): p. 2138-46.
82. Al-Swiahb, et al., Prognostic Impact of p16, p53, Epidermal Growth Factor Receptor, and Human Papillomavirus in Oropharyngeal Cancer in a Betel Nut±Chewing Area. Arch Otolaryngol Head Neck Surg, 2010. 136(5): p. 502-508.
83. Alos, L., et al., Human papillomaviruses are identified in a subgroup of sinonasal squamous cell carcinomas with favorable outcome. Cancer, 2009. 115(12): p. 2701-2709.
84. Kuo, K.T., et al., The biomarkers of human papillomavirus infection in tonsillar squamous cell carcinoma-molecular basis and predicting favorable outcome. Mod Pathol, 2008. 21(4): p. 376-86.
85. Fakhry, C., et al., Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst, 2008.
100(4): p. 261-269.
86. Klozar, J., et al., HPV status and regional metastasis in the prognosis of oral and oropharyngeal cancer. Eur Arch Otorhinolaryngol, 2008. 265 Suppl 1: p. S75-82.
87. Smith, E.M., et al., Human papillomavirus, p16 and p53 expression associated with survival of head and neck cancer. Infect Agent Cancer, 2010. 5: p. 4.
88. Badaracco W, et al., Molecular analyses and prognostic relevance of HPV in head and neck tumours. Oncology reports, 2007. 17: p. 931-939.
89. Jo S, et al., Human Papillomavirus Infection as a Prognostic Factor in Oropharyngeal Squamous Cell Carcinomas Treated in a Prospective Phase II Clinical Trial. Anticancer research, 2009. 29: p. 1467-1474.
90. Chernock R.D, et al., Human Papillomavirus±Related Squamous Cell Carcinoma of the Oropharynx. Arch Otolaryngol Head Neck Surg, 2011. 137(2): p. 163-169.
91. Smith E.M, et al., p16INK4a Expression, human papillomavirus, and survival in head and neck cancer. Oral Oncology, 2008. 44: p. 133-142.
92. Lindquist, D., et al., Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7. Mol Oncol, 2007. 1(3): p. 350-5.
93. Iglesias-Bartolome R, Martin D, and G. J.G, Exploiting the Head and Neck Cancer Oncogenome: Widespread PI3K-mTOR Pathway Alterations and Novel Molecular Targets Cancer Discovery, July 2013 3.
94. Lui, V.W., et al., Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov, 2013. 3(7): p. 761-9.
95. Fei, J., et al., Prognostic significance of vascular endothelial growth factor in squamous cell carcinomas of the tonsil in relation to human papillomavirus status and epidermal growth factor receptor. Ann Surg Oncol, 2009. 16(10): p. 2908-2917.
96. Ritta, M., et al., Cell cycle and viral and immunologic profiles of head and neck squamous cell carcinoma as predictable variables of tumor progression. Head Neck, 2009. 31(3): p. 318-27.
97. Kong, C.S., et al., The relationship between human papillomavirus status and other molecular prognostic markers in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys, 2009. 74(2): p. 553-61.
98. Sedaghat, A.R., et al., Prognostic significance of human papillomavirus in oropharyngeal squamous cell carcinomas. Laryngoscope, 2009. 119(8): p. 1542-9.
99. Na, II, et al., EGFR mutations and human papillomavirus in squamous cell carcinoma of tongue and tonsil. Eur J Cancer, 2007. 43(3): p. 520-6.
100. Jung, A.C., et al., Biological and clinical relevance of transcriptionally active human papillomavirus (HPV) infection in oropharynx squamous cell carcinoma. Int J Cancer, 2010.
170
101. Sugiyama, M., et al., Human papillomavirus-16 in oral squamous cell carcinoma: clinical correlates and 5-year survival. Br J Oral Maxillofac Surg, 2007. 45(2): p. 116-22.
102. Weinberger, P.M., et al., Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis. J Clin Oncol, 2006. 24(5): p. 736-47.
103. De Petrini M, et al., Head and neck squamous cell carcinoma: role of the human papillomavirus in tumour progression. The new microbiologica, 2006. 29: p. 25-33.
104. Dahlgren, L., et al., Comparative genomic hybridization analysis of tonsillar cancer reveals a different pattern of genomic imbalances in human papillomavirus-positive and -negative tumors. Int J Cancer, 2003. 107(2): p. 244-249.
105. Li, W., et al., Human papillomavirus positivity predicts favourable outcome for squamous carcinoma of the tonsil. Int J Cancer, 2003. 106(4): p. 553-8.
106. Mellin, H., et al., Human papillomavirus type 16 is episomal and a high viral load may be correlated to better prognosis in tonsillar cancer. Int J Cancer, 2002. 102(2): p. 152-8. 107. Ringström E, et al., Human Papillomavirus Type 16 and Squamous Cell Carcinoma of the
Head and Neck. Clin Cancer Res, 2002. 8: p. 3187-3192.
108. Haraf D J, et al., Human papilloma virus and p53 in head and neck cancer: clinical correlates and survival. Clin Cancer Res, 1996. 2: p. 755-762.
109. Koutcher, L.D., et al., Cisplatin (CDDP) and Radiation (RT) versus Cetuximab (C) and RT in the Context of Human Papillomavirus (HPV) and P16 in the Treatment of Locally Advanced Head and Neck Cancer (LAHNC). International Journal of Radiation Oncology*Biology*Physics, 2010. 78(3): p. S63.
110. Badaracco, et al., Molecular analyses and prognostic relevance of HPV in head and neck tumours. Oncology Reports, 2007. 17: p. 931-939.
111. Hoffmann M, et al., Human papillomaviruses in head and neck cancer: 8 year-survival-analysis of 73 patients. Cancer Letters, 2005. 218(2): p. 199-206.
112. Azzimonti, et al., Altered patterns of the interferon-inducible gene IFI16 expression in head